Quantum chemical study of gas-phase reactions of isoprene with OH radicals producing highly oxidised second-generation products.

The formation of secondary organic aerosols caused by atmospheric oxidation of isoprene is harmful to human health and the climate; thus, isoprene oxidation is further mandatory to obtain less harmful or harmless highly oxidised products. In this numerical investigation, 2-hydroperoxy-2-methylbut-3-en-1-ol (ISOPOOH) was considered the model compound to investigate the formation of three RO2 radicals (C5H11O4, C5H11O6 and C5H11O5) and two saturated highly oxidised products (C5H12O6 and C5H10O6). The complete reaction network and its thermodynamics and kinetics were analysed to obtain the most probable and feasible reaction pathways. Four different levels of theories (HF, B3LYP, M06-2X and ωB97XD with basis set of 6-31+g(d,p)) were employed to explore a global minimum of ISOPOOH. All theories provided approximately close energetics; however, because of the novelty of the functional and parameterisation of the basis set, the ωB97XD functional was selected to examine the reaction mechanism. C5H12O6 was formed as the second-generation highly oxidised product during ISOPOOH oxidation.

Bone mineral density among long-term survivors of childhood acute lymphoblastic leukemia: results from the St. Jude Lifetime Cohort Study.

BACKGROUND: The prevalence of low bone mineral density (BMD) in adult survivors of childhood acute lymphoblastic leukemia (ALL), and the degree of recovery or decline, are not well elucidated. PROCEDURE: Study subjects (age ≥ 18 years and ≥10 years post-diagnosis) participated in an institutional follow-up protocol and risk-based clinical evaluation based on Children's Oncology Group guidelines. Trabecular volumetric BMD was ascertained using quantitative computed tomography, reported as age- and sex-specific Z-scores. RESULTS: At median age 31 years, 5.7% of 845 subjects had a BMD Z-score of ≤-2 and 23.8% had a Z-score of -1 to -2. Cranial radiation dose of ≥24 Gy, but not cumulative methotrexate or prednisone equivalence doses, was associated with a twofold elevated risk of a BMD Z-score of ≤-1. The cranial radiation effect was stronger in females than in males. In a subset of 400 subjects, 67% of those who previously had a BMD Z-score of ≤-2 improved by one or more categories a median of 8.5 years later. CONCLUSIONS: Very low BMD was relatively uncommon in this sample of adult survivors of childhood ALL, and BMD Z-scores tended to improve from adolescence to young adulthood. High-dose cranial or craniospinal radiation exposure was the primary predictor of suboptimal BMD in our study. Given that cranial radiation treatment for childhood ALL is used far more sparingly now than in earlier treatment eras, concerns about persistently low BMD among most current childhood ALL patients may be unwarranted.

Parental risk perception and influenza vaccination of children in daycare centres.

Little information is available about perceptions of influenza vaccination of parents with healthy children in daycare. Therefore, we systematically explored the relationship between parental risk perception and influenza vaccination in children attending daycare. We distributed a self-administered paper survey to parents of children aged 6-59 months attending licensed daycare centres in Tarrant County, Texas. We used conditional logistic regression with penalized conditional likelihood to estimate odds ratios (ORs) and 95% profile likelihood confidence limits (PL) for parental risk-perception factors and influenza vaccination. A high level of parental prevention behaviours (OR 9.1, 95% PL 3.2, 31) and physician recommendation (OR 8.2, 95% PL 2.7, 30) had the highest magnitudes of association with influenza vaccination of healthy children in daycare. Our results provide evidence about critical determinants of influenza vaccination of healthy children in daycare, which could help inform public health interventions aimed at increasing influenza vaccination coverage in this population.

Statistical characterization of the forces on spheres in an upflow of air.

The dynamics of a sphere fluidized in a nearly levitating upflow of air were previously found to be identical to those of a Brownian particle in a two-dimensional harmonic trap, consistent with a Langevin equation [Ojha et al., Nature (London) 427, 521 (2004)]. The random forcing, the drag, and the trapping potential represent different aspects of the interaction of the sphere with the air flow. In this paper we vary the experimental conditions for a single sphere, and report on how the force terms in the Langevin equation scale with air flow speed, sphere radius, sphere density, and system size. We also report on the effective interaction potential between two spheres in an upflow of air.

Statistical mechanics of a gas-fluidized particle.

Characterization of the microscopic fluctuations in systems that are far from equilibrium is crucial for understanding the macroscopic response. One approach is to use an 'effective temperature'--such a quantity has been invoked for chaotic fluids, spin glasses, glasses and colloids, as well as non-thermal systems such as flowing granular materials and foams. We therefore ask to what extent the concept of effective temperature is valid. Here we investigate this question experimentally in a simple system consisting of a sphere placed on a fine screen in an upward flow of gas; the sphere rolls because of the turbulence it generates in the gas stream. In contrast to many-particle systems, in which it is difficult to measure and predict fluctuations, our system has no particle-particle interactions and its dynamics can be captured fully by video imaging. Surprisingly, we find that the sphere behaves exactly like a harmonically bound brownian particle. The random driving force and frequency-dependent drag satisfy the fluctuation-dissipation relation, a cornerstone of statistical mechanics. The statistical mechanics of near-equilibrium systems is therefore unexpectedly useful for studying at least some classes of systems that are driven far from equilibrium.

Low-speed impact craters in loose granular media.

We report on craters formed by balls dropped into dry, noncohesive, granular media. By explicit variation of ball density rho(b), diameter D(b), and drop height H, the crater diameter is confirmed to scale as the 1/4 power of the energy of the ball at impact: D(c) approximately equal (rho(b)D(3)(b)H)(1/4). Against expectation, a different scaling law is discovered for the crater depth: d approximately equal (rho(3/2)(b)D(2)(b)H)(1/3). The scaling with properties of the medium is also established. The crater depth has significance for granular mechanics in that it relates to the stopping force on the ball.

Molecular dynamics simulation study of DNA triplex formed by mixed sequences in solution.

The unrestrained molecular dynamics simulation of the triple helical DNA with mix sequences d(GACTGGTGAC).d(CTGACCACTG)*d (GACTGGTGAC), using the particle mesh Ewald sum, is presented here. The Ewald summation method effectively eliminates the usualcut-of of the long range interactions and allowed us to evaluate the full effect of the electrostatic forces. The AMBER5.0 force field has been used during the simulation in solvent. The MD results support a dynamically stable model of DNA triplex over the entire length of the trajectory. The duplex structure assumes the conformation, which is very close to B-DNA. In mixed sequences the purine bases occurs in both strand of DNA duplex. The bases of third strand do not favor the Hoogsteen or/and reverse Hoogsteen type of Hydrogen bonding but they form hydrogen bonds with the bases of both the strand of DNA duplex. The orientation of the third strand is parallel to one of the strand of duplex and all nucleotides (C, A, G & T) show isomorphic behavior with respect to the DNA duplex. The conformation of all the three strands is almost same except few exceptions. Due to interaction of third strand the conformational change in the duplex structure and a finite amount of displacement in the W-C base pairs have been observed. The conformational variation of the back bone torsion angles and helicoidal parameters, groove widths have been discussed. The sequence dependent effects on local conformation, helicoidal and morphological structure, width of the grooves of DNA helix may have important implication for understanding the functional energetics and specificity of interactions of DNA and its triplexes with proteins, pharmaceutical agents and other ligands.

DNA bending and sequence-dependent backbone conformation NMR and computer experiments.

Although DNA bending plays a crucial role in several biological processes, very little is known experimentally about the relationship between sugar phosphate conformation and sequence directed bending. In this paper, we determine the coupling constants for a nonself-complementary 11-mer A-tract DNA duplex from 2D NMR experiments and along each chain of the duplex, we report the sugar pucker, torsional preferences and conformational averaging about the C3'-O3', C4'-C5' and C5'-O5' bonds for each nucleotide. The A-tract exists as an equilibrium blend of canonical B-form and noncanonical B-form in which the exocyclic C4'-C5' bond is in trans conformation as in the original Watson-Crick model [Crick, F.H.C. & Watson, J.D. (1954) Proc. Roy. Soc. (London), A223, 80-96]. The trans conformation at the C4'-C5' can increase the interphosphate distance and lead to local unwinding of the duplex and rolling of the base pair into the major groove. This will create a kink or hinge. At the 3'-end of the A-tract in the purine-thymine step, the duplex is compressed by the presence of a junction between A and B forms of DNA exclusively in one strand, with consequent reduction of the phosphate-phosphate distance. The coupling constant data seriously disagree with the A-tract DNA bending model of Crothers [Koo, H.-S., Wu, H.-M. & Crothers, D.M. (1986) Nature 320, 501-506], but is in agreement with the finding of Leroy et al. [Leroy, J.-L., Charretier, E., Kochoyan, M. & Gueron, M. (1988) Biochemistry 27, 8894-8898] that the structure that drives bending in the A-tract is locally different from B-DNA. Structural distortions are extremely localized with little or no propagation. It is likely that transcription factor proteins recognize these preexisting deformations in the free DNA itself and mold it into the matrix of the protein.

An investigation of the conformation of peptide-T and its D-Ala analog by NMR and molecular dynamics simulations.

Peptide-T (ASTTTNYT) and its D-Ala analog (D-ASTTTNYT-NH2) have been designed to block the adsorption of HIV to CD4 receptors on T-cell lymphocytes, thus inhibiting viral infectivity. The conformation of these important peptides has been investigated by 2D-NMR and molecular dynamics simulations. The NMR studies in DMSO show that the peptides exist in solution as a mixture of conformations. beta-Turns and non-specific folded conformations are present in a small proportion in the ensemble of conformations, which is largely dominated by more or less extended structures. This result is in line with molecular dynamics simulations where beta-turns were found to occur with a low frequency and with energies 10 to 17 kcal/mole higher than the global minimum structure. Our findings differ from previous reports on the conformation of peptide-T determined by NMR.

Structure of an anti-HIV-1 hammerhead ribozyme complex with a 17-mer DNA substrate analog of HIV-1 gag RNA and a mechanism for the cleavage reaction: 750 MHz NMR and computer experiments.

The structure of an anti-HIV-1 ribozyme-DNA abortive substrate complex was investigated by 750 MHz NMR and computer modeling experiments. The ribozyme was a chimeric molecule with 30 residues-18 DNA nucleotides, and 12 RNA residues in the conserved core. The DNA substrate analog had 17 residues. The chimeric ribozyme and the DNA substrate formed a shortened ribozyme-abortive substrate complex of 47 nucleotides with two DNA stems (stems I and III) and a loop consisting of the conserved core residues. Circular dichroism spectra showed that the DNA stems assume A-family conformation at the NMR concentration and a temperature of 15 degrees C, contrary to the conventional wisdom that DNA duplexes in aqueous solution populate entirely in the B-form. It is proposed that the A-family RNA residues at the core expand the A-family initiated at the core into the DNA stems because of the large free energy requirement for the formation of A/B junctions. Assignments of the base H8/H6 protons and H1' of the 47 residues were made by a NOESY walk. In addition to the methyl groups of all T's, the imino resonances of stems I and III and AH2's were assigned from appropriate NOESY walks. The extracted NMR data along with available crystallographic data, were used to derive a structural model of the complex. Stems I and III of the final model displayed a remarkable similarity to the A form of DNA; in stem III, a GC base pair was found to be moving into the floor of the minor groove defined by flanking AT pairs; data suggest the formation of a buckled rhombic structure with the adjacent pair; in addition, the base pair at the interface of stem III and the loop region displayed deformed geometry. The loop with the catalytic core, and the immediate region of the stems displayed conformational multiplicity within the NMR time scale. A catalytic mechanism for ribozyme action based on the derived structure, and consistent with biochemical data in the literature, is proposed. The complex between the anti HIV-1 gag ribozyme and its abortive DNA substrate manifests in the detection of a continuous track of A.T base pairs; this suggests that the interaction between the ribozyme and its DNA substrate is stronger than the one observed in the case of the free ribozyme where the bases in stem I and stem III regions interact strongly with the ribozyme core region (Sarma, R. H., et al. FEBS Letters 375, 317-23, 1995). The complex formation provides certain guidelines in the design of suitable therapeutic ribozymes. If the residues in the ribozyme stem regions interact with the conserved core, it may either prevent or interfere with the formation of a catalytically active tertiary structure.

Interaction energy studies on antibiotics nucleoside analogs 2-azaadenine.

The 2-azaadenine antibiotic is known to be a potent cytotoxic nucleoside analog. Evaluation of the interaction energy of this molecule with nucleic acid bases and base pairs has been performed using a quantum-mechanical perturbation technique. Both in-plane and stacking energies have been computed. These energy values along with their sites of association have been compared with the standard energy values and spatial positions for the nucleic acid bases during transcription. The results have been examined in the light of their biological significance.

Biological activity of 3-deazauridine nucleoside analogue: a theoretical study.

The incorporation model of Sanyal et al. has been used to understand the biological activity of the cytostatic compound 3-deazauridine. The interaction energies of various types of binding pattern of the enterant molecule with nucleic acid fragments have been computed. The energy values and the sites of association of the analogous base, obtained by optimization of energy values as well as the sites of association of nucleic acid bases during the transcription process have been compared. The specificity of the binding of the interacting molecule has been discussed, along with the inhibitory effect of 3-deazauridine. They are in agreement with the experimentally observed evidence.

Amsacrine binds in a cooperative manner to deoxyribonucleic acid.

The intercalative binding of the acridine antitumour drug 4'-(9-acridinylamino) methane-sulphonate-m-anisidine, a known inhibitor of nucleic acid synthesis, to native calf thymus DNA has been studied using optical titration method. Amsacrine (AMSA) exhibits positive cooperativity in their equilibrium binding to DNA as indicated by the positive slope in the initial region of the binding isotherms (Scatchard plots) under conditions simulating physiological ionic strengths. m-AMSA binds with a higher degree of cooperativity than o-AMSA. Although this correlates with the effectiveness of the drugs as antitumour agents, the exact relationship between the observation of cooperative binding and pharmacological activity is yet to be determined.

Mode of action of intercalators: a theoretical study.

Mode of action of some intercalators has been theoretically investigated on the basis of quantum mechanical perturbation method. Energies of H-bond interaction between drug chromophore and base pairs have been calculated in all possible orientations. The stacking energy has also been calculated with the base pairs. The effect of these interactions on specific recognition has also been discussed. On the basis of these studies, a model for the interaction of these drugs has been proposed. This explains the relative activities of acridine intercalators and satisfies the experimental observations.

Interaction energy studies of an antimetabolite 8-azaguanine during transcription.

The possible incorporation of 8-azaguanine during transcription has been examined in the light of the model of transcription developed earlier by Sanyal et al. Electrostatic energy of interaction has been calculated for the nucleoside analogue (8-azaguanine) base for the entire space inside the deep groove of the DNA double helix. The interaction energy values and the location of the possible sites of association are compared with the recommended configurations of RNA transcription. It is concluded that 8-azaguanine is capable of replacing guanine during transcription. These conclusions are in general agreement with the experimental results.

Molecular basis of drug action of some antibiotics.

A molecular model for the role of nucleoside or nucleotide analogs in drug action has been developed. This model, an extension of our earlier model has been employed to examine the possibility of incorporation of the formycin class of antibiotics (formycin, formycin B and oxoformycin B) in the growing RNA chain. Interaction energy of the analogous bases has been computed for the entire available space inside the deep groove of the DNA double helix. The values of the interaction energy thus computed along with the location of the sites of possible association are compared with the recommended configuration for RNA during transcription. It has been found that only formycin which structurally and energy-wise fulfils the requirement of the model, can successfully replace adenosine during transcription. Results are in agreement with experimental findings.